title: Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.
abstract: The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/β HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.
authors.affiliation: Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, Illkirch, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Marek
authors.forename: Srinivasaraghavan
authors.initials: S
authors.lastname: Kannan
authors.forename: Alexander-Thomas
authors.initials: AT
authors.lastname: Hauser
authors.forename: Marina
authors.initials: M
authors.lastname: Moraes Mourão
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Caby
authors.forename: Vincent
authors.initials: V
authors.lastname: Cura
authors.forename: Diana A
authors.initials: DA
authors.lastname: Stolfa
authors.forename: Karin
authors.initials: K
authors.lastname: Schmidtkunz
authors.forename: Julien
authors.initials: J
authors.lastname: Lancelot
authors.forename: Luiza
authors.initials: L
authors.lastname: Andrade
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Renaud
authors.forename: Guilherme
authors.initials: G
authors.lastname: Oliveira
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.forename: Christophe
authors.initials: C
authors.lastname: Romier
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D015801:Helminth Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012550:Schistosoma mansoni / Q000201:enzymology* / Q000235:genetics
chemical_list: D015801:Helminth Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases